Clozapine, sold under the brand name Clozaril among others,
Clozapine is associated with a relatively high risk of low white blood cells (agranulocytosis), a condition of suppressed immunity which may result in death.
Clozapine was first made in 1958 and sold commercially in 1972.
Contents
1 Medical uses
2 Side effects
2.1 Agranulocytosis
2.2 Cardiac toxicity
2.3 Gastrointestinal hypomotility
2.4 Hypersalivation
2.5 Central nervous system
2.6 Urinary incontinence
2.7 Withdrawal effects
2.8 Weight gain and diabetes
3 Interactions
4 Pharmacology
4.1 Pharmacodynamics
4.2 Pharmacokinetics
5 Chemistry
6 History
7 Society and culture
7.1 Brand names
8 See also
9 References
10 Further reading
11 External links
Medical uses
Clozapine is an atypical antipsychotic drug primarily used in people who are unresponsive to or intolerant to other antipsychotics.
In a 2013 study in a comparison of 15 antipsychotic drugs in effectiveness in treating schizophrenic symptoms, clozapine was ranked first and demonstrated very high effectiveness. 25% more effective than amisulpride (2nd), 33% more effective than olanzapine (3rd), and twice as effective as haloperidol, quetiapine, and aripiprazole.
The effect of clozapine, however, is not (at least in the short term) reflected in measures of global functioning such as ability to leave the hospital and maintain an occupation. The relapse rate is lower and patient acceptability is better.
It may be better than other antipsychotics in people with both schizophrenia and Parkinson’s disease.
Clozapine is not recommended for the treatment of behavior problems in older adults with dementia.
Side effects
Clozapine may cause side effects, some of which are serious and potentially fatal. Common side effects include constipation, bed-wetting, night-time drooling, muscle stiffness, sedation, tremors, orthostatic hypotension, hyperglycemia, and weight gain. The risk of developing extrapyramidal symptoms, such as tardive dyskinesia is below that of typical antipsychotics; this may be due to clozapine’s anticholinergic effects. Extrapyramidal symptoms may subside somewhat after a person switches from another antipsychotic to clozapine.
Clozapine carries five black box warnings, including warnings for agranulocytosis, central nervous system depression, leukopenia, neutropenia, seizure disorder, bone marrow suppression, dementia, hypotension, myocarditis, orthostatic hypotension (with or without syncope ) and seizures.
Many male patients have experienced cessation of ejaculation during orgasm as a side effect of clozapine, though this is not documented in official drug guides.
However, many side-effects can be managed and do not necessarily warrant discontinuation.
Agranulocytosis
Main article: Agranulocytosis
Clozapine carries a black box warning for drug-induced agranulocytosis. Without monitoring, agranulocytosis occurs in about 1% of people who take clozapine during the first few months of treatment;
Clozapine-induced agranulocytosis can be transient.
Cardiac toxicity
Myocarditis is a sometimes fatal side effect of clozapine, which usually develops within the first month of commencement.
Gastrointestinal hypomotility
Another underrecognized and potentially life-threatening side effect spectrum is gastrointestinal hypomotility, which may manifest as severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.
Hypersalivation
While clozapine is a muscarinic antagonist at the M1, M2, M3, and M5 receptors, clozapine is a full agonist at the M4 subset. Because M4 is highly expressed in the salivary gland, its M4 agonist activity is thought to be responsible for the hypersalivation.
Central nervous system
CNS side effects include drowsiness, vertigo, headache, tremor, syncope, sleep disturbances, nightmares, restlessness, akinesia, agitation, seizures, rigidity, akathisia, confusion, fatigue, insomnia, hyperkinesia, weakness, lethargy, ataxia, slurred speech, depression, myoclonic jerks, and anxiety. Rarely seen are delusions, hallucinations, delirium, amnesia, libido increase or decrease, paranoia and irritability, abnormal EEG, worsening of psychosis, paresthesia, status epilepticus, and obsessive compulsive symptoms. Similar to other antipsychotics clozapine rarely has been known to cause neuroleptic malignant syndrome.
Urinary incontinence
Clozapine is linked to urinary incontinence,
Withdrawal effects
Abrupt withdrawal may lead to cholinergic rebound effects, severe movement disorders as well as severe psychotic decompensation. It has been recommended that patients, families, and caregivers are aware of the symptoms and risks of abrupt withdrawal of clozapine. When discontinuing clozapine, gradual dose reduction is recommended to reduce the intensity of withdrawal effects.
Weight gain and diabetes
In addition to hyperglycemia, significant weight gain is frequently experienced by patients treated with clozapine.
Interactions
Fluvoxamine inhibits the metabolism of clozapine leading to significantly increased blood levels of clozapine.
When carbamazepine is concurrently used with clozapine, it has been shown to decrease plasma levels of clozapine significantly thereby decreasing the beneficial effects of clozapine.
Published case reports have stated that the use of benzodiazepines and clozapine concomitantly can result in severe adverse reaction such as respiratory arrest, cardiac arrest and sudden death.
Ciprofloxacin is an inhibitor of CYP1A2 and clozapine is a major CYP1A2 substrate. Randomized study reported elevation in clozapine concentration in schizophrenia subjects concurrently taking ciprofloxacin.
Pharmacology
Pharmacodynamics
See also: Atypical antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications
Clozapine (and metabolite)
Site
CZP
NDMC
5-HT 1A
123.7
13.9
5-HT 1B
519
406.8
5-HT 1D
1,356
476.2
5-HT 2A
5.35
10.9
5-HT 2B
8.37
2.8
5-HT 2C
9.44
11.9
5-HT 3
241
272.2
5-HT 5A
3,857
350.6
5-HT 6
13.49
11.6
5-HT 7
17.95
60.1
α 1A
1.62
104.8
α 1B
7
85.2
α 2A
37
137.6
α 2B
26.5
95.1
α 2C
6
117.7
β 1
5,000
6,239
β 2
1,650
4,725
D 1
266.25
14.3
D 2
157
101.4
D 3
269.08
193.5
D 4
26.36
63.94
D 5
255.33
283.6
H 1
1.13
3.4
H 2
153
345.1
H 3
>10,000
>10,000
H 4
665
1,028
M 1
6.17
67.6
M 2
36.67
414.5
M 3
19.25
95.7
M 4
15.33
169.9
M 5
15.5
35.4
σ 1
5,000
>10,000
σ 2
ND
>10,000
MOR
1,000
>10,000
DOR
1,000
127.9
KOR
1,000
>10,000
SERT
1,624
316.6
NET
3,168
493.9
DAT
>10,000
>10,000
Values are K i (nM). The smaller the value, the more strongly the drug binds to the site. All data are for human cloned proteins, except σ 1 (guinea pig), MOR (rat), DOR (mouse), and KOR (guinea pig).
Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors.
Clozapine is an antagonist at the 5-HT 2A subunit of the serotonin receptor, putatively improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia.
A direct interaction of clozapine with the GABA B receptor has also been shown.
Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes,
Pharmacokinetics
N – desmethylclozapine (norclozapine), clozapine’s major active metabolite.
The absorption of clozapine is almost complete following oral administration, but the oral bioavailability is only 60 to 70% due to first-pass metabolism. The time to peak concentration after oral dosing is about 2.5 hours, and food does not appear to affect the bioavailability of clozapine.
The elimination half-life of clozapine is about 14 hours at steady state conditions (varying with daily dose).
Clozapine is extensively metabolized in the liver, via the cytochrome P450 system, to polar metabolites suitable for elimination in the urine and feces. The major metabolite, norclozapine ( desmethyl -clozapine), is pharmacologically active. The cytochrome P450 isoenzyme 1A2 is primarily responsible for clozapine metabolism, but 2C, 2D6, 2E1 and 3A3/4 appear to play roles as well. Agents that induce (e.g., cigarette smoke) or inhibit (e.g., theophylline, ciprofloxacin, fluvoxamine ) CYP1A2 may increase or decrease, respectively, the metabolism of clozapine. For example, the induction of metabolism caused by smoking means that smokers require up to double the dose of clozapine compared with non-smokers to achieve an equivalent plasma concentration.
Clozapine and norclozapine (desmthyl-clozapine) plasma levels may also be monitored, though they show a significant degree of variation and are higher in women and increase with age.
Chemistry
Clozapine is a dibenzodiazepine that is structurally related to loxapine. It is slightly soluble in water, soluble in acetone, and highly soluble in chloroform. Its solubility in water is 0.1889 mg/L (25 °C).
History
Clozapine was synthesized in 1958 by Wander AG, a Swiss pharmaceutical company, based on the chemical structure of the tricyclic antidepressant imipramine. The first test in humans in 1962 was considered a failure. Trials in Germany in 1965 and 1966 as well as a trial in Vienna in 1966 were successful. In 1967 Wander AG was acquired by Sandoz.
In 2015 the individual manufacturer Patient Registries were consolidated by FDA request into a single shared Patient Registry Called The Clozapine REMS Registry.
Society and culture
Brand names
Clozapine is sold under many brands worldwide including Alemoxan, Azaleptine, Azaleptol, Cloment, Clonex, Clopin, Clopine, Clopsine, Cloril, Clorilex, Clozamed, Clozapex, Clozapin, Clozapina, Clozapine, Clozapinum, Clozapyl, Clozarem, Clozaril, Denzapine, Dicomex, Elcrit, Excloza, FazaClo, Froidir, Ihope, Klozapol, Lanolept, Lapenax, Leponex, Lodux, Lozapine, Lozatric, Luften, Medazepine, Mezapin, Nemea, Nirva, Ozadep, Ozapim, Refract, Refraxol, Schizonex, Sensipin, Sequax, Sicozapina, Sizoril, Syclop, Syzopin, Tanyl, Uspen, Versacloz, Xenopal, Zaclo, Zapenia, Zapine, Zaponex, Zaporil, Ziproc, and Zopin.
See also
DHA-clozapine
Drug of last resort

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